EP1596838A2

EP1596838A2 - Once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent

Info

Publication number: EP1596838A2
Application number: EP04705487A
Authority: EP
Inventors: Sunil Sadanand Nadkarni
Original assignee: Torrent Pharmaceuticals Ltd
Current assignee: Torrent Pharmaceuticals Ltd
Priority date: 2003-02-11
Filing date: 2004-01-27
Publication date: 2005-11-23
Also published as: WO2004071374A2; WO2004071374A3

Abstract

Once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, the proton pump inhibitor is as delayed release and the prokinetic agent is as sustained release, having improved patient compliance and process of preparing the pharmaceutical compositions.

Description

ONCE A DAY ORALLY ADMINISTERED PHARMACEUTICAL COMPOSITIONS

Field of Invention

The invention relates to once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, the proton pump inhibitor is as delayed release and the prokinetic agent is as sustained release. The invention results in reduced dosing frequency and improved patient compliance. This invention further relates to a process for preparing the dosage form. Background of the invention Proton pump inhibitors and prokinetic agents are commonly used and co- prescribed in the treatment of gastroesophageal reflu diseases and various other gastrointestinal conditions including erosive esophagitis, pathological hypersecretory conditions, gastrointestinal ulcers, dyspepsia, gastroparesis, intestinal pseudo- obstruction and post-operative ileus. Proton pump inhibitor for example, Esomeprazole, the S-isomer of Omeprazole, is the first proton pump inhibitor synthesized as an optical isomer to become available for clinical use. Esomeprazole suppresses the final step in gastric acid production by binding to two sites of the (it, K⁺)-ATPase enzyme system at the secretory surface of the gastric parietal cell. It provides better acid control than current racemic proton pump inhibitors (lansoprazole, pantoprazole and rabeprazole) and has a favorable pharmacokinetic profile relative to omeprazole. The duration of antisecretory effect that persists for longer than 24 hours which makes it a useful drug in peptic ulcer disease and gastro-esophageal reflux disorder. The proton pump inhibitors are generally administered once a day due to their long duration of antisecretory effect. Proton pump inhibitors are, however, susceptible to degradation/transformation in acidic and neutral media. The half-life of degradation of omeprazole in water solutions at pH-values less than three is shorter than ten minutes. The degradation of omeprazole is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and to some degree by light.

In respect to the stability properties of proton pump inhibitors, it is obvious that proton pump inhibitors in an oral solid dosage form must be protected from contact with the acidic gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption of proton pump inhibitors can occur.

Prokinetic agent for example, mosapride , which exerts its action via 5-HT₄ receptors. It enhances peristaltic efficiency thus enhancing gastrointestinal motility and gastric emptying. Thus, it is used for treating non-ulcer dyspepsia, gastroparesis, gastric stasis and gastroesophageal reflux disease (GERD). Mosapride has a bioavailability of 8% and has elimination half-life of 1.4 to 2.0 hrs (www.micromedex.com). Hence, conventional release formulation cannot maintain required plasma concentration for long time and is therefore given 3-4 times a day(Drugs of the future, 1993, 513-515). It is a safe drug. Most of the studies have reported no serious side effects of mosapride even at higher dose (Drugs Res., 1993, 867-872 J Pharmacol Expt ther, 1997, 220-227). Mosapride is a selective 5-HT receptor agonist and does not interact with other receptor types. It has a very favorable tolerability profile, with only minor adverse effects such as headache. Unlike other prokinetic agents, mosapride does not cause extrapyramidal symptoms or endocrine disorders. Although, there were rare reports of mosapride associated with QT interval prolongation, the reported incidences occurred when mosapride was used with other pro-arrhythmic drugs. Prior Art

WO 97/25065 discloses the oral pharmaceutical dosage forms comprising a proton pump inhibitor and a prokinetic agent. Various examples of dosage forms are given in which the proton pump inhibitor is in the form of delayed release and the prokinetic agent is in the form of immediate release.

The persons skilled in the art would appreciate that even though the unit dosage having said combination as per WO 97/25065 is given to a patient, the real purpose of combination as mentioned in the said patent will not be served. The said patent, though indicates (line no. 12 to 19) that "administration of two, three or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results", the number of tablets that has to be given based on the said patent are more than one, for the simple reason that the pro-kinetic agent in the formulation is in conventional form. The pro-kinetic agent, for example, mosapride has elimination half- life of 1.4 to 2 hours. Hence, the unit dosage given to the patient will not be sufficient for once a day regimen i.e. mosapride has to be given to the patient for two times even after the original unit dosage. Thus, the patient at the end of the day would have to take three tablets (first of unit dosage, second of conventional mosapride and third again for conventional mosapride).

WO 99/51583 discloses methods and compositions using (+) norcisapride in combination with proton pump inhibitors or H₂ receptor antagonists. The invention specifically gives examples of combination of immediate release (+) norcisapride and a proton pump inhibitors or H₂ receptor antagonist. As discussed above it also does not disclose the method to manufacture the dosage form in which the prokinetic agent is in the form of modified release. Merely specifying that the modified release formulation of (+) norcisapride can be manufactured as per the prior art can not result in an effective modified release formulation.

WO 99/51584 discloses methods and compositions using (-) norcisapride in combination with proton pump inhibitors or H₂ receptor antagonists. The invention specifically give examples of combination of immediate release (-) norcisapride and a proton pump inhibitors or H₂ receptor antagonist. As discussed above it also does not disclose the method to manufacture the dosage form in which the prokinetic agent is in the form of modified release. Merely specifying that the modified release formulation of (-) norcisapride can be manufactured as per the prior art can not result in an effective modified release formulation.

European patent EP 1060743 Al discloses oral cisapride dosage forms with an extended action. It further discloses the method to enhance the solubility of cisapride at above neutral pH in order to make bioavailable systems which, can provide efficient plasma levels of cisapride over 24 hours. The invention does not disclose use of other prokinetic agents or their combination with proton pump inhibitors.

WO 96/29055 teaches about pectin based pharmaceutical compositions used for the prevention of gastric reflux. It forms a stable gel raft in the gastric environment. It may further contain one or more agents selected from antacids, antibiotics, anti-emetic, proton pump inhibitors, etc.

WO 99/51209 teaches the art of making press coated pulsatile release formulations. The formulation first provides a substantially first order delivery of active ingredient followed by pulsed delivery of an increased amount of the active ingredient.

Patent application US 2001/0051185 Al discloses an osmotic pump containing controlled release ranitidine in the core. The formulation also contains a prokinetic agent, which is in the form of rapid release and at least 75% of the prokinetic agent is released within one hour. Therefore the formulation may not maintain the effective plasma concentration of the prokinetic agents having short half life for a period of 24 hours if given once daily.

WO 98/29095 discloses a sustained release cisapride oral dosage form suitable for once daily administration. The formulation comprises plurality of mini tablets containing organic acid. The release of cisapride through mini tablets is dependent on the pH of the aqueous environment.

Prior art discloses many different types of dosage forms containing proton pump inhibitor and prokinetic agent in unit dosage form. There are no examples describing any compositions which contains combination of a proton pump inhibitor in the form of delayed release and a prokinetic agent in the form of sustained release, and the dosage form maintains the plasma concentration for the period of 24 hours so that it can be administered once a day. Thus, there exists a need for once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, the proton pump inhibitor is as delayed release and the prokinetic agent is as sustained release, and the formulation with improved patient compliance

Considering the above aspects, a sustained release formulation of prokinetic agent for example, mosapride would be of great use. The potential advantages of sustained release mosapride over conventional mosapride are as follows Φ Increased patient compliance because of less frequent drag administration.

Φ The sustained therapeutic plasma levels with this formulation would be maintained for 24 hours. This would make the drug administration meal independent and would also prevent the regurgitation (GERD) even during sleep. The proton pump inhibitors and prokinetic agents are frequently co-prescribed in the management of GERD and other gastrointestinal conditions mentioned above.

Prokinetic agents prevent reflux, while, proton pump inhibitors reduce acid secretion. Thus, the combination has complementary action in abating the symptomatology and in controlling the acid-pepsin and motility related diseases. The combination of a proton pump inhibitor and a prokinetic agent, where the proton pump inhibitor is as delayed release and the prokinetic agent is as sustained release will provide following advantages over the available dosage forms:

$ Similar duration of action of proton pump inhibitor and sustained release prokinetic agent. Φ Ease of administration and better compliance because of single daily administration.

Φ Effective in controlling nocturnal esophageal reflux due to prolonged duration of action. Φ No overlap in adverse drug reactions. The combination will have the lower possible daily therapeutic dose of the respective drugs, which makes it less vulnerable to cause any sorts of side effects. Φ No Adverse drug interaction.

Combining two active ingredients in one pharmaceutical unit to improve patient compliance is known in literature. It can be either in the form of two or more active ingredients in immediate release form or a combination of immediate release, delayed release and sustained release form. There are various techniques by which the combination of delayed release and sustained release is formulated in single dosage form but this does not always lead to an effective dosage form. It is known to the person skilled in the art that the various factors like type of dosage form, in vitro release profile and in vivo parameters are very important to make a dosage form effective.

Accordingly, a need exists for once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, the proton pump inhibitor is as delayed release and the prokinetic agent is as sustained release. The invention results in a dosage form, which is effective, reduces dosing frequency and improves patient compliance. Further, the dosage form should be simple and economical to produce. Objects of the invention Therefore, it is an object of the present invention to provide a once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, wherein the proton pump inhibitor is as delayed release and the prokinetic agent is as sustained release.

Another object of the present invention is a dosage form, which is suitable for swallowing for humans containing two active ingredients one of which is in delayed release form and other in sustained release form.

Furthermore, the formulations according to the invention provide a further significant advantage with respect to tablet or simple capsule. People who need to swallow a tablet or a capsule under the above mentioned conditions may sometimes have to swallow the said tablet or capsule without water and that can be dangerous as the tablet or capsule can get into trachea i.e. respiratory side.

Further object of the invention is to provide independent sustained release formulation of pro-kinetic agent.

It is yet another object of present invention to provide a once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, which can provide an improved pharmacokinetic profile. An improved pharmacokinetic profile here means that the formulation will provide a more constant blood level of drug and will show less fluctuation between the maximum and minimum plasma drug concentration than once or repeated doses of regular / immediate release drug formulation containing equal amounts of active ingredients administered per day.

A further objective of the present invention is a formulation, which gives accurate dosing and is prepared by simple processes. Summary of the invention

The above and other objects of the present invention are acheived by providing a once a day orally administered pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent, which can provide an improved pharmacokinetic profile. An improved pharmacokinetic profile here means that the formulation will provide a more constant blood level of drug and will show less fluctuation between the maximum and minimum plasma drug concentration than once or repeated doses of regular/immediate release drug formulation containing equal amounts of active ingredients administered per day. Formulations according to the aspect of the present invention are particularly useful in administration of medications to individuals who cannot or will not chew or swallow, such as debilitated patients, patients who have difficulty swallowing solids, and elderly. Detailed Description of the Invention "Sustained release" refers to the release of an agent such as a drug from a composition or dosage form in which the agent is released according to a desired profile over an extended period of time. Sustained release profiles include, for example, controlled release, prolonged release, pulsatile release, and delayed release profiles. In contrast to immediate release compositions, controlled release compositions allow delivery of an agent to a subject over an extended period of time according to predetermined profile. Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacological or diagnostic response as compared to conventional rapid release dosage forms. Such longer periods of response provide for many inherent benefits that are not achieved with the corresponding short acting, immediate release preparations. For example, in the treatment of chronic pain, controlled release formulations are often highly preferred over conventional short-acting formulations. Sustained release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drags, medicaments, active agents, diagnostic agents, or any substance to be internally administered to an animal, including humans. A sustained release composition is typically used to improve the effects of administered substances by optimizing the kinetics of delivery, thereby increasing bio-availability, convenience, and patient compliance, as well as minimizing side effects associated with inappropriate immediate release rates such as a high initial release rate and, if undesired, uneven blood or tissue levels.

The term "immediate release" as used herein in relation to the composition according to the invention or used in any other context means release which is not modified release and releases more than 70% of the antidiabetic active ingredient within 60 minutes. The term "immediate release dosage form" as used herein can be described as dosage form which allows the drag to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drag (as per US FDA guideline for 'SUPAC-MR: Modified Release Solid Oral Dosage Forms').

The term "dosage form" denotes any form of the formulation that contains an amount sufficient to achieve a therapeutic effect with a single administration.

"Delayed release" refers to restricted dissolution of the active ingredient from the dosage form in the stomach but not in intestine, there by allowing dosage form transit through stomach and drag dissolution and absorption from the intestines. The delayed release is obtained by enteric coating. The enteric coating is employed in case if the drug is destroyed by gastric acid, is irritating to gastric mucosa or when by pass of stomach enhances drag absorption from intestine to a significant extent. The term "enteric coat / polymeric coat" is defined for the purpose of the present invention as a coat with substance which is insoluble at a pH value of less than 4.5 and is soluble at a pH value of greater than 5.5.

"Proton pump inhibitors" refers to any agent or compound that inhibits or suppresses gastric acid secretion by inhibition of H⁺ -K⁺ ATPase enzyme system at the secretary surface of gastric parietal cells.

"Prokinetic agents" refers to active ingredients which effectively increases esophageal peristalsis and lower esophageal sphincter pressure, increases gastric motility and peristalsis, enhances gastroduodenal co-ordination and consequently facilitates gastric emptying and decreases small bowl transit time.

The term "swallowing" as used herein is essentially synonymous with "ingestion". The pharmaceutical compositions of the instant invention can be in the form of a tablet, a capsule, a multiparticulate form, or a unit dose packet (sometimes referred to in the art as a "sachet"). The term "tablet" is intended to embrace compressed conventional tablets, coated tablets, multiparticulate tablet, matrix tablets, bilayered tablets, multilayered tablets, tablet-in-tablet, inlay tablets, and other forms known in the art. The representative examples of some of these formulations are shown in figures 4, 5, 6, 1 and 8. The term "capsule" is intended to embrace capsules in which the body of the capsule disintegrates after ingestion to release particulate contents. The capsule may contain particles or tablets of two or more types or combinations thereof. The representative examples of some of these formulations are shown in figures 1, 2, 3 and 9. The term "multiparticulate" is intended to embrace a dosage form comprising a multiplicity of particles whose totality represents the intended therapeutically useful dose of proton pump inhibitor and prokinetic agent. The particles generally are of a diameter from about 100 microns to about 0.3 cm, with a preferred range of 150 microns to 1.5 mm. The use of these and other terms is more fully set out below. Multiparticulates represent a preferred embodiment for sustained-release because they are particularly useful in administration of medications to individuals who cannot or will not chew or swallow, such as debilitated patients, patients who have difficulty swallowing solids. These can be taken without water or can be dispersed in water for the convenience of the patients. A multiparticulate can have numerous formulation applications. For example, a multiparticulate may be used as a powder for filling a capsule shell, or used per se for mixing with food (e.g., ice cream) to increase palatability. In a further aspect, this invention provides a process for preparing dosage forms comprising a proton pump inhibitor and a prokinetic agent, the proton pump inhibitor is as delayed release and the proldnetic agent is as sustained release.

The pharmaceutical composition of unit dosage form can be prepared, but not restricted, in following steps: Step- 1 : Preparation of proton pump inhibitor part. Step-2: Preparation of prokinetic agent part.

Step-3: Preparation of unit dosage while combining the product obtained by step-1 and step-2. Prokinetic Agent Part: The prokinetic agent part of this invention is in the form of sustained release. The sustained release of the proldnetic agent can be achieved through various classes of dosage forms. For purposes of discussion, not limitation, the many embodiments hβreunder can be grouped into classes according to design and principle of operation viz: (a) prokinetic agent is embedded or dispersed in a matrix (b) bilayered matrix tablet

(c) core coated with rate controlling membrane(s)

A first class includes matrix tablet, in which the proldnetic agent is embedded or dispersed in a matrix of another material that serves to retard the release of proldnetic agent into an aqueous environment (i.e., the lumenal fluid of the Gl tract). When prokinetic agent is dispersed in a matrix of this sort, release of the drug takes place principally from the surface of the matrix. Thus the drag is released from the surface of a device which incorporates the matrix after it diffuses through the matrix or when the surface of the device erodes, exposing the drug. In some embodiments, both mechanisms can operate simultaneously. The matrix system can be hydrophilic or hydrophobic.

The preferred embodiment of a matrix system has 'the form of a hydrophilic matrix tablet comprising prokinetic agent and an amount of hydrophilic polymer sufficient to provide a useful degree of control over the prokinetic agent dissolution. Hydrophilic polymers useful for forming the matrix include hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), poly (ethylene oxide), poly(vinyl alcohol), xanthan gum, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate or mixture of components selected from these. A preferred material is HPMC. Other similar hydrophilic polymers may also be employed. In use, the hydrophilic material is swollen by, and eventually dissolves, in water. The prokinetic agent is released both by diffusion from the matrix and by erosion of the matrix. The prokinetic agent dissolution rate of these hydrophilic matrix tablets may be controlled by the amount and molecular weight of hydrophilic polymer employed. In general, using a greater amount of the hydrophilic polymer decreases the dissolution rate, as does using a higher molecular weight polymer. Using a lower molecular weight polymer increases the dissolution rate. The dissolution rate may also be controlled by the use of water-soluble additives such as sugars, salts, or soluble polymers. Examples of these additives are sugars such as lactose, sucrose, or mannitol, salts such as NaCI, KCl, NaHCO3, and water soluble polymers such as PVP, low molecular weight HPC or HMPC or methyl cellulose. In general, increasing the fraction of soluble material in the formulation increases the release rate. A matrix tablet typically comprises about 1 to 95% by weight of prokinetic agent and about 99 to 5% by weight of polymer.

The matrix tablet can also include one or more commonly used excipients in oral pharmaceutical formulations.

Representative commonly used excipients in oral pharmaceutical formulations include povidone, starch, talc, fumed silica, glyceryl monostearate, magnesium stearate, calcium stearate, kaolin, colloidal silica, gypsum, Polysorbate 80 (Tween 80), micronised silica and magnesium trisilicate. The quantity of commonly used excipients in oral pharmaceutical formulations used is from about 0.1% to about 10% by weight, preferably from 0.25 to 7.5%. based on the total weight of the formulation.

A preferred matrix tablet comprises, by weight, about 2.5% to about 50% prokinetic agent, about 10% to about 75% HPMC, 2.5% to about 75% lactose, 0.5% to about 10% PNP, 0.25% to about 5% talc, 0.25% to about 2% colloidal silicon dioxide and about 0.25% to about 2% magnesium stearate.

The granules of the matrix formulation can be manufactured in accordance with usual granulation techniques in which the prokinetic agent and other excipients are mixed and granulated by adding solution of binder in a low or high shear mixer or by fluidized bed granulation. The granulate is dried, preferably in a fluidized bed dryer. The dried granulate is sieved and mixed with lubricants and disintegrants. Alternatively the manufacture of granules of matrix formulation can be made by direct mixing of the directly compressible excipients or by roller compaction. The granules can be compressed into tablets using conventional tablet compression machine using specified toolings.

A wide variety of prokinetic agents may be used in combination with a suitable proton pump inhibitor in the fixed unit dosage form according to the present invention. Such proldnetic agents include, for example, cisapride, dazopride, mosapride, exepanol, lintopride, motilin, idremcinal, mitemcinalum, neurotrophin-3, KC-11458, MKC-733, Braintree-851, zacopride, ecabapide, pracalopride, fedotozine, cinitapride, itopride, polycarbophil, tegaserod, INKP-100, diacol, metoclopramide and domperidone. A preferable proldnetic agent for the new fixed dosage form is mosapride or domperidone. Such suitable prokinetic agents are described in EP 0 243 959 and EP 0 076 530, the disclosures of which are each incorporated herein by express reference thereto.

The second class of formulation includes a bilayered matrix tablet, in which an immediate release layer containing prokinetic agent is compressed with matrix formulation described above. The immediate release layer releases the prokinetic agent immediately and helps in achieving initial high drug levels in plasma, the layer formed by matrix formulation releases prokinetic agent at predetermined rate for extended duration. A bilayered matrix tablet typically comprises about 0 to 50 % by weight of total prokinetic agent in immediate release layer and about 100 to 50% by weight of total prokinetic agent in sustained release layer, preferably about 5 to 45 % by weight of total prokinetic agent in immediate release layer and about 95 to 55% by weight of total prokinetic agent in sustained release layer and more preferably about 10 to 40 % by weight of total prokinetic agent in immediate release layer and about 90 to 60% by weight of total prokinetic agent in sustained release layer. . The immediate release layer of the bilayered matrix tablet comprises prokinetic agent and auxiliary excipients such as diluents, binders, lubricants, surfactants, disintegrants, plasticisers, anti-tack agents, opacifying agents, pigments, and such like. As will be appreciated by those skilled in the art, the exact choice of excipients and their relative amounts will depend to some extent on the final oral dosage form.

Suitable diluents include for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, starch, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as those sold under the Trade Mark Avicel PH 101, Avicel PH 102, Avicel PH 112, Avicel PH 200, Avicel PH301 and Avicel PH 302, lactose such as lactose monohydrate, lactose anhydrous and Pharmatose DCL21 (Pharmatose is a Trade Mark), including anhydrous, monohydrate and spray dried forms, dibasic calcium phosphate such as Emcompress (Emcompress is a Trade Mark), mannitol, Pearlitol SD 200 (Pearlitol SD 200 is a trade mark), starch, sorbitol, sucrose, and glucose.

Suitable binders include for example starch, povidone, hydroxypropylmethylcellulose, pregelatinised starch, hydroxypropylcellulose and/or mixtures of the foregoing.

Suitable lubricants, including agents that act on the flowability of the powder to be compressed are, for example, colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a Trade Mark), talc, stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate. Suitable disintegrants include for example lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate and combinations and mixtures thereof.

The granules of the immediate release layer can be manufactured as per procedures described above. The compression of tablets is carried out on usual machines designed to compress bilayered tablets (e.g. machines of the Manesty, Cadmach or Kilian) using specified tooling.

The third class of formulations of prokinetic agents are multiparticulate systems. These are sustained release particles of prokinetic agents comprising of core coated with rate controlling membrane(s).

The core comprises of prokinetic agent along with commonly used water soluble and/or water insoluble and/or water dispersible and/or water disintegrable excipients and optionally comprising of rate controlling excipient(s). In core, the prokinetic agent and the excipient(s) are preferably present in a ratio of from 1:100 to 100:1, more particularly from 1:10 to 10:1.

The prokinetic agent and excipient(s) are preferably built up on a central inert nucleus. The inert nucleus suitably consists of an inert component such as a non-pareil bead of sugar, sugar/starch or microcrystalline cellulose having an average diameter in the range of from 0.05 to 0.75 mm, typically from 0.15 to 0.3 mm. The actual nucleus size used may vary depending on the drug loading required for particular formulation. The core may be built up in a conventional coating pan. Alternatively, the drug and polymeric material may be built up on a central inert nucleus as herein before defined in an automated coating system for example, wurster coater.

According to one embodiment the rate-controlling membrane or micro matrix is made up of pharmaceutically acceptable polymer(s) of varying water solubility or water permeability. The rate controlling membrane or micro matrix can be combination of polymers of low water permeability/solubility polymer(s) and high permeability/solubility polymer(s).

The polymers that can be used to form the rate-controlling membrane or micromatrix are described in greater detail herein below.

The rate controlling polymer(s) are selected from alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic acids and esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene terephthalates, polyvinyl esters, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurethanes and copolymers thereof.

According to an especially preferred embodiment the rate-controlling membrane contains ammonio methacrylate co-polymers as hereinafter described.

The term high water soluble/permeable polymer as used herein includes polymers such as Eudragit RL. Likewise, the term low water soluble/permeable polymer as used herein includes polymers, such as Eudragit RS.

The high water soluble/permeable polymer is suitably polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose or polyethylene glycol or a mixture thereof.

The low water soluble/permeable polymer is suitably ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(mefhyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly (hexyl methacrylate), poly(isodecyl methacrylate), poly (lauryl methacrylate), poly(phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), or a mixture thereof.

A suitable polymer, which is freely permeable to aqueous solution of prokinetic agent and water, is a polymer sold under the Trade Mark Eudragit RL. The suitable polymers, which are slightly permeable to aqueous solution of prokinetic agent and water, are polymers sold under the Trade Mark Eudragit RS and Eudragit NE 30D or a polymer whose permeability is pH dependent such as those sold under the Trade Marks Eudragit L, Eudragit S or Eudragit E. Eudragit polymers are polymeric lacquer substances based on acrylate and/or methacrylates.

The polymeric coating used to form the rate-controlling membrane can also include one or more commonly used excipients in oral pharmaceutical formulations.

Representative commonly used excipients in oral pharmaceutical formulations include talc, fumed silica, glyceryl monostearate, magnesium stearate, calcium stearate, kaolin, colloidal silica, gypsum, Tween 80, Geleol pastiles (trade mark), micronised silica and magnesium trisilicate. The quantity of commonly used excipients in oral pharmaceutical formulations used is from about 1% to about 50% by weight, preferably from 2 to 40% based on the total dry weight of the polymer.

The polymeric coating can also include a material that improves the processing of the polymers. Such materials are generally referred to as "plasticisers" and include, for example, adipates, azelates, benzoates, citrates, isoebucaes, phthalates, sebacates, stearates, tartrates, polyhydric alcohols and glycols.

Representative plasticisers include acetylated monoglycerides, butyl phthalyl butyl gylcolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate,, ethyl phthalyl ethyl glycolate, glycerin, ethylene glycol, propylene glycol, triethyl citrate, triacetin, tripropinoin, diacetin, dibutyl phthalate, acetyl monoglyceride, polyethylene glycols, castor oil, triethyl citrate, polyhydric alcohols, acetate esters; glycerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylexyl phthalate, di-n-octyl phthalate, di-I-octyl phthalate, di-I-decyl phthalate, di- n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylexyl trimellitate, di-2-efhylexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate and glyceryl monocaprate. The amount of plasticiser to be used is from about 1% to 50% based on the weight of the dry polymer(s).

The amount of polymer(s) to be used in forming the particles will be determined based on various parameters such as the desired delivery properties, including the amount of drug to be delivered, the drag release rate desired, and the size of the particles. The membrane polymers will be coated to 1 to 100% weight gain on the cores, preferably 5 to 70% polymer weight gain. The rate controlling membrane on the particles, including all solid components thereof such as co-polymer, filler, plasticiser and optional commonly used excipients and processing aids, is from about 1% to 150% weight gain on the cores, preferably 5% to 80% weight gain. The rate controlling polymer membrane can be coated by any known method, including spray application. Spraying can be carried out using a fluidized bed coated (preferably Wurster coating), or in a pan coating system.

The core is suitably coated with a polymeric rate-controlling membrane comprising at least one polymeric material as described above. The core may be coated to a coating level that is sufficient to facilitate the desired release rate.

The rate-controlling membrane can comprise a single polymer or a mixture of two or more polymers.

The rate controlling polymer of the membrane is any one of those herein above specified for the core and includes polymers with varying solubility and permeability to water. .

The multiparticulate formulation of prokinetic agent can be in the form of a multiparticulate formulation or a tablet. A multiparticulate oral dosage form according to the invention can comprise a blend of one or more populations of particles, pellets or mini-tablets having different invitro and/or invivo release characteristics. For example, the multiparticulate oral dosage form can comprise a blend of an instant or fast release component and controlled release component compressed into rapidly disintegrating tablet. Fast release component and/or controlled release component can additionally be coated with an enteric coating polymer membrane. Alternatively the blend of instant or fast release and controlled release component contained in a suitable capsule, for example hard or soft gelatin capsules. The multiparticulate formulation may be filled into a capsule and may be administered by swallowing the capsule or by opening said capsule and sprinkling the contents onto food. Alternatively the multiparticulate formulation may be presented in a sachet.

Proton Pump Inhibitor Part: The proton pump inhibitor part of this invention is in the form of delayed release. The delayed release of the proton pump inhibitor can be achieved through various classes of dosage forms. For purposes of discussion, not limitation, the many embodiments hereunder can be grouped into classes according to design and principle of operation viz:

(a) multiparticulate system

(b) enteric coated tablet

A first class includes multiparticulate system, in which proton pump inhibitor is in the form of enteric coated particles. The core material for the individually enteric coated particles can be constituted according to different principles. Seeds layered with proton pump inhibitor, optionally mixed with alkaline reacting compounds, can be used as the core material for further processing.

Proton pump inhibitors include, but not limited to, benzimidazole derivatives, such as omeprazole, rabeprazole, pantoprozole, lansoprazole, pariprazole_? leminoprazole, nepaprazole, tenatoprazole, esomeprazole or active metabolites thereof.

The proton pump inhibitors used in the dosage forms of the invention may be used in neutral form or in the form of an alkaline salt, such as for instance the Mg²⁺,

Ca ⁺, Na⁺, K⁺ or Li⁺ salts preferably the Mg²⁺ salts. Further where applicable, the compounds listed above may be used in racemic form or in the form of a substantially pure enantiomer thereof, or alkaline salts of the single enantiomers.

Suitable proton pump inhibitors are for example disclosed in EP-A 1-0005129,

EP-A1-174 726, EP-A1-166 287, GB 2 163 747, WO 90/06925, WO91/19711,

WO91/19712, WO95/01977, WO94/27988 and US patent numbers 4,544,750, 4,620,008, 4,758,579, 5,045,552, 5,374,730, 5,386,032, 5,47,983, 5,502,195, the disclosures of which are each incorporated herein by express reference thereto.

The gastric acid suppressing agent is preferably an acid susceptible proton pump inhibitor but other gastric acid suppressing agents such as the H₂ receptor antagonists: ranitidine, nizatidine, cimeditine or famotidine may be used together with a prokinetic agent in the pharmaceutical compositions according to the present invention. Suitable H₂ receptor antagonists are disclosed in US patent numbers 5,541,335, 5,700,945, 5,118,813, 4,413,129, 4,855,439, 4,886,910 and 4,886,912, the disclosures of which are each incorporated herein by express reference thereto.

The seeds, which are to be layered with the proton pump inhibitor, can be water insoluble seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures or water soluble seeds comprising different inorganic salts, sugars, non-pareils and other materials, alone or in mixtures. Optionally the seeds can be coated with a barrier layer(s) (seal coating) comprising pharmaceutical excipients optionally including alkaline compounds such as for instance pH-buffering compounds. Further, the seeds may comprise active substance in the form of crystals, agglomerates, compacts etc. The size of the seeds may vary between approximately 0.1 and 2 mm. The seeds layered with active substance are produced either by powder or solution/suspension layering using for instance granulating or spray coating/layering equipment.

Before the seeds are layered, the active substance may be mixed with further components. Such components can be binders, surfactants, fillers, disintegrating agents, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures.

The binders are for example celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and carboxymethyl-cellulose sodium, polyvinyl pyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in the groups of pharmaceutically acceptable non-ionic or ionic surfactants such as for instance sodium lauryl sulfate.

Alternatively, proton pump inhibitor optionally mixed with alkaline compounds and further mixed with suitable constituents can be formulated into core material. Said core materials may be produced by extrusion/spheronization, balling or compression utilizing different process equipment. The proton pump inhibitor is mixed with pharmaceutical constituents to obtain preferred handling and processing properties and a suitable' concentration of the active substance in the final mixture. Pharmaceutical constituents such as fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives, can be used.

The proton pump inhibitor may also be mixed with an alkaline pharmaceutically acceptable substance(s). Such substances can be chosen among, but are not restricted to, substances such as sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; aluminium hydroxide/sodium bicarbonate coprecipitate, substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as disodium hydrogen orthophosphate and similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.

The core material is coated with a barrier layer comprising pharmaceutical excipients optionally including alkaline compounds such as for instance pH-buffering compounds. This barrier layer separates the core material from the outer layer(s), the outer layer(s) being enteric coating layer(s).

The barrier layer can be applied to the core material by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the separating layer can be applied to the core material by using powder coating technique. The materials for separating layers are pharmaceutically acceptable compounds such as, for instance, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacldng and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the separating layer.

One or more enteric coating layers are applied onto the core material covered with separating layer by using a suitable coating technique. The enteric coating layer material may be dispersed or dissolved in either water or in suitable organic solvents. As enteric coating layer polymers one or more, separately or in combination, of the following can be used; e.g. solutions or dispersions of methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating layer polymer(s). The enteric coating layers contain pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers. Additives such as dispersants, colorants, pigments, polymers e.g. poly(ethylacrylat, mefhylmefhacrylate), anti-tacking and anti-foaming agents may also be included into the enteric coating layer(s). The enteric coated particles can be cured in hot air oven.

Particles covered with enteric coating layer(s) may further be covered with one or more over-coating layer(s). The over-coating layer(s) can be applied to the enteric coating layered pellets by coating or layering procedures in suitable equipment such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating or layering process. The materials for over-coating layers are chosen among pharmaceutically acceptable compounds such as, for instance sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the over-coating layer(s). Said over-coating layer may further prevent potential agglomeration of enteric coating layered pellets, further protect the enteric coating layer towards cracking during the compaction process and enhance the tableting process. The maximum thickness of the applied over-coating layer(s) is normally only limited by processing conditions. The second class includes enteric coated tablet, in which the granules of proton pump inhibitor are prepared and the granules are compressed to tablets. The tablets of proton pump inhibitor are coated with barrier coat followed by enteric coating. The granules comprise proton pump inhibitor and auxiliary excipients such as for example diluents, alkaline substances, binders, lubricants, surfactants, disintegrants, plasticisers, anti-tack agents, opacifying agents, pigments, as described above. The granules and the tablets are prepared as per the methods described above. The barrier coat and enteric coat can be done as per the method described above and using the appropriate excipients described above.

Preparation of Unit Dosage Form: The sustained release prokinetic part and delayed release proton pump inhibitor part prepared above are combined to form unit dosage form. Capsule: The combination of one type of formulation of prokinetic agent part such as single layer tablet, bilayered tablet or multiparticulate system and one type of formulation of proton pump inhibitor part such as enteric coated tablet or enteric coated multiparticulate systems, as prepared above, are filled in hard gelatin capsules using automatic or semiautomatic capsule filling machines fitted with suitable change parts. The possible combinations of prokinetic agent part and proton pump inhibitor part, but not limited to, can be tablet and tablet, pellets and pellets, pellet and tablet, tablet and pellets, filled in one capsule. More than one tablet of prokinetic agent or proton pump inhibitor can be filled in one capsule. Some of these combinations are shown in figures 1, 2, 3 and 9. Tablet: The combination of one type of formulation of prokinetic agent part such as single layer tablet, bilayered tablet or multiparticulate system and one type of formulation of proton pump inhibitor part such as enteric coated tablet or enteric coated multiparticulate systems, as prepared above, can be done in the form of different types of tablets such as, but not limited to, single layer tablets (consisting of proldnetic agent and proton pump inhibitor in the form of multiparticulate system), bilayered tablet (consisting of matrix tablet of proldnetic agent as one layer and other layer of proton pump inhibitor in the form of multiparticulate system along with excipients), multilayer tablet (consisting of a bilayered tablet of prokinetic agent and third layer of proton pump inhibitor in the form of multiparticulate system along with excipients), tablet-in- tablet and inlay tablets using tablet compression machines fitted with suitable change parts. Some of these combinations are shown in figures 4, 5, 6, 7 and 8.

The multiparticulate system of prokinetic agent and proton pump inhibitor alone or in combination and one or more auxiliary excipient materials can be compressed into tablet form. The formulations of the present invention may comprise auxiliary excipients such as for example diluents, lubricants, surfactants, disintegrants, plasticisers, anti-tack agents, opacifying agents, pigments, flavourings and such like. As will be appreciated by those skilled in the art, the exact choice of excipient and their relative amounts will depend to some extent on the final oral dosage form.

Suitable diluents include, for example pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of the foregoing. Examples of diluents include microcrystalline celluloses such as those sold under the Trade Mark Avicel PH 101, Avicel PH 102, Avicel PH 112, Avicel PH 200, Avicel PH301 and Avicel PH 302, lactose such as lactose monohydrate, lactose anhydrous and Pharmatose DCL21 (Pharmatose is a Trade Mark), including anhydrous, monohydrate and spray dried forms, dibasic calcium phosphate such as Emcompress (Emcompress is a Trade Mark), mannitol, Pearlitol SD 200 (Pearlitol .SD 200 is a trade mark), starch, sorbitol, sucrose and glucose.

Suitable lubricants, including agents that act on the flowability of the powder to be compressed are, for example, colloidal slilcon dioxide such as Aerosil 200 (Aerosil is a Trade Mark), talc, stearic acid, magnesium stearate, calcium stearate and sodium stearyl fumarate. Suitable disintegrants include for example lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate and mixtures thereof.

In a preferred embodiment, the prokinetic agent of the pharmaceutical composition can exhibit following invitro dissolution profile when measured as per the specified conditions- from 5 to 70% prokinetic agent is released in one hour, from 15 to 80 % prokinetic agent is released in four hours, from 25 to 90 % prokinetic agent is released in eight hours, from 35 to 100 % prokinetic agent is released in twelve hours.

In a preferred embodiment, the proton pump inhibitor of the pharmaceutical composition can exhibit following invitro dissolution profile in 0.1 N HCl or simulated gastric fluid when measured as per the specified conditions- not more than 15 % proton pump inhibitor is release in two hours.

In a preferred embodiment, the proton pump inhibitor of the pharmaceutical composition can exhibit following invitro dissolution profile in simulated intestinal fluid or appropriate buffer when measured as per the specified conditions- not less than 75 % proton pump inhibitor is release in 45 minutes.

A once a day orally administered pharmaceutical compositions of the present invention comprising a proton pump inhibitor and a prokinetic agent, which can be talcen without water or can be dispersed in water for the convenience of the patients. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross section of capsule dosage form, it comprises delayed release pellets of a proton pump inhibitor (1) and a bilayered tablet (2) of a prokinetic agent having immediate release layer (4) and sustained release layer (3) filled in hard gelatin capsule shell.

FIG. 2 is a cross section of capsule dosage form, it comprises delayed release pellets of a proton pump inhibitor (1) and sustained release pellets (5) of a prokinetic agent filled in hard gelatin capsule shell.

FIG. 3 is a cross section of capsule dosage form, it comprises two tablets filled in hard gelatin capsule shell. One tablet (6) comprising delayed release pellets of a proton pump inhibitor (1) in admixture with excipients (7) and a bilayered tablet (2) of a prokinetic agent having immediate release layer (4) and sustained release layer (3).

FIG. 4 is a cross section of tablet dosage form, it comprises delayed release pellets of a proton pump inhibitor (1) and sustained release pellets (5) of a prokinetic agent compressed into tablet along with pharmaceutically acceptable excipients (7).

FIG. 5 is a cross section of bilayered tablet dosage form, it comprises one layer of delayed release pellets of a proton pump inhibitor (1) in admixture with pharmaceutically acceptable excipients (7) and second layer (8) of a prokinetic agent in sustained release form. FIG. 6 is a cross section of multilayered tablet dosage form. It comprises one layer of delayed release pellets of a proton pump inhibitor (1) in admixture with pharmaceutically acceptable excipients (7) and second layer (4) and third layer (3) of a prokinetic agent in sustained release and immediate release form respectively.

FIG. 7 is a cross section of inlay tablet dosage form. It comprises delayed release pellets of a proton pump inhibitor (1) in admixture with pharmaceutically acceptable excipients (7) as outer portion and a bilayered inlay tablet of a prokinetic agent containing one sustained release layer (4) and one immediate release layer (3). FIG. 8 is a cross section of tablet-in-tablet dosage form. It comprises delayed release pellets of a proton pump inhibitor (1) in admixture with pharmaceutically acceptable excipients (7) as outer portion and a bilayered tablet of a prokinetic agent containing one sustained release layer (4) and one immediate release layer (3)as inner portion.

FIG. 9 is a cross section of capsule dosage form, it comprises two tablets filled in hard gelatin capsule shell. One tablet comprising a proton pump inhibitor in tablet core (9) coated with seal coat and an enteric coat (10) and a bilayered tablet (2) of a prokinetic agent having immediate release layer (4) and sustained release layer (3). Different modes for practicing the invention.

The following examples further illustrate but by no means limit the present invention.

The dissolution of dosage forms of the present invention was determined by following method. For mosapride-

Instrument - Apparatus II, USP (paddle)

Revolution - 50 / min.

Temperature - 37±0.5°C

Dissolution medium - 900 ml 0.1 N HCl For domperidone-

Instrument - Apparatus II, USP (paddle)

Revolution - 50 / min.

Temperature - 37±0.5°C

Dissolution medium - 900 ml 0.01 N HCl containing 1 % SLS For esomeprazole (gastric resistance) -

Instrument - Apparatus II, USP (paddle)

Revolution - 100 / min.

Temperature - 37±0.5°C

Dissolution medium - 900 ml 0.1 N HCl For esomeprazole (dissolution in simulated intestinal fluid) -

Instrument - Apparatus II, USP (paddle)

Revolution - 100 / min.

Temperature - 37±0.5°C Dissolution medium - 900 ml pH 6.8 KH₂PO₄ buffer

For omeprazole (gastric resistance) -

Instrument - Apparatus II, USP (paddle)

Revolution - 100 /min. Temperature - 37±0.5°C

Dissolution medium - 900 ml 0.1 N HCl

For omeprazole (dissolution in simulated intestinal fluid) - Instrument - Apparatus II, USP (paddle) Revolution - 100 / min.

Temperature - 37±0.5°C

Dissolution medium - 900 ml pH 6.8 KH₂PO₄ buffer

For rabeprazole sodium (gastric resistance) -

Instrument - Apparatus II, USP (paddle) Revolution - 100 / min.

Temperature - 37±0.5°C

Dissolution medium - 900 ml 0.1 N HCl

For rabeprazole sodium (dissolution in simulated intestinal fluid) - Instrument - Apparatus II, USP (paddle) Revolution - 100 / min.

Temperature - 37±0.5°C

Dissolution medium - 900 ml pH 10.0 borate buffer

Examples

The present invention will now be described in greater detail with reference to the following illustrative but non limiting examples. The pharmaceutical composition of unit dosage form can be prepared, but not restricted, in following steps. Step-1 : Preparation of proton pump inhibitor part. Step-2: Preparation of proldnetic agent part.

Step-3 Preparation of unit dosage while combining the product obtained by step-1 and step-2.

Example 1 1) Proton pump inhibitor part a) Drug coated pellets- Drag suspension was prepared using esomeprazole magnesium trihydrate, hydroxypropylmethyl cellulose and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with microcrystalline cellulose (Celphere CP 305) and it was coated by spraying the drag

5 suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting drag coated pellets were sieved through sieves 710 μm and 425 μm. The pellets passed through sieve 710 μm and retained on sieve 425 μm were used. Composition of drag coated pellets: 101. Microcrystalline cellulose 35.30 %w/w (Celphere CP 305)

2. Esomeprazole magnesium 51.76 %w/w trihydrate

3. Hydroxypropyl Methylcellulose 12.94 %w/w (E-15 LV)

15 b) Barrier coated pellets- Barrier coating suspension was prepared using magnesium stearate, hydroxypropylmethyl cellulose and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with drag coated pellets from step 1(a) and it was coated by spraying the barrier coating suspension. The

20 spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting barrier coated pellets were sieved through sieves 710 μm and 425 μm. The pellets passed through sieve 710 μm and retained on sieve 425 μm were used. Composition of barrier coated pellets:

25 ^' 1. Drug coated pellets 86.96 %w/w

2. Magnesium stearate 2.17 %w/w

3. Hydroxypropyl Methylcellulose 10.87 %w/w (E-15 LV) c) Enteric coated pellets-I - Enteric coating suspension was prepared using methacrylic 30 acid copolymer, type C USP-NF (Eudragit L 30 D-55), talc, polyethylene glycol 6000 and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with barrier coated pellets from step 1(b) and it was coated by spraying the enteric coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting enteric coated pellets-I were sieved through sieves 710 μm and 425 μm. The pellets passed through sieve 710 μm and retained on sieve 425 μm were used. Composition of enteric coated pellets-I:

1. Barrier coated pellets 65.55 %w/w

2. Eudragit L30D 55 30.49 %w/w

3. Polyethylene glycol 6000 0.91 %w/w

4. Talc 3.05 %w/w

d) Enteric coated pellets-II - Enteric coating suspension was prepared using methacrylic acid copolymer, type C USP-NF (Eudragit L 30 D-55), triethyl citrate, glyceryl monopalmitostearate (Geleol pastilles), Tween 80 and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with barrier coated pellets from step 1(c) and it was coated by spraying the enteric coating suspension. The spraymg operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried in the fluid bed processor. The resulting enteric coated pellets-II were sieved through sieves 850 μm and 425 μm. The pellets passed through sieve 850 μm and retained on sieve 425 μm were used. Composition of enteric coated pellets-II:

1. Enteric coated pellets-I 45.24 %w/w

2. Eudragit L30D 55 49.50 %w/w

3. Triethyl citrate 4.45 %w/w 4. Tween 80 0.07 %w/w 5. Geleol pastilles 0.74 %w/w

2) Prokinetic agent part a) Immediate release portion- 4.76 %w/w of mosapride citrate dihydrate was mixed with 55.00 %w/w of lactose monohydrate, 32.14 %w/w microcrystalline cellulose, 0.02 %w/w ferric oxide red, 0.08 %w/w ferric oxide yellow and the mixture was granulated with 3.00 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 1.0 %w/w magnesium stearate, 3.5 %w/w croscarmellose sodium, and 0.50 % w/w colloidal silicon dioxide. b) Sustained release portion- 13.90 %w/w of mosapride citrate dihydrate was mixed with 47.98 %w/w of lactose monohydrate and 31.25 %w/w hydroxypropyl methylcellulose K4M and the mixture was granulated with 5.00 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 1.25 %w/w magnesium stearate, 0.62%w/w colloidal silicon dioxide. c) Tablet compression- 100 mg granules prepared in step 2(a) and 80 mg granules prepared in step 2(b) were compressed to 180 mg weight bilayered tablets having a diameter of 5.56 mm.

3) Capsule filling

10 Proton pump inhibitor part equivalent to 40 mg esomeprazole prepared in step 1 and proldnetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step 2 were filled in size 2 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 was determined (Table 1) Table 1: Dissolution profile of capsule

15

Example 2 1) Proton pump inhibitor part

Same as for Example 1 202) Prokinetic agent part a) Immediate release portion- Same as for Example 1 b) Sustained release portion- Same as for Example 1 c) Tablet compression- 100 mg granules prepared in step 2(a) and 80 mg granules prepared in step 2(b) were compressed to 180 mg weight bilayered tablets having a

25 diameter of 7.14 mm.

3) Capsule filling Proton pump inhibitor part equivalent to 40 mg esomeprazole prepared in step 1 and prokinetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step 2 were filled in size 00 hard gelatin capsule. The dissolution rate of the dosage form prepared in step 3 was determined (Table 2):

Table 2: Dissolution profile of capsule

Eicample 3 1) Proton pump inhibitor part a) Seal coated pellets- Seal coating suspension was prepared using ethyl cellulose 10 cps, talc, methanol and methylene chloride. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with sugar globules and it was coated by spraying the seal coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting drug coated pellets were sieved through sieves 850 μm and 600 μm. The pellets passed through sieve 850 μm and retained on sieve 600 μm were used. Composition of seal coated pellets: 1. Sugar globules 93.28 %w/w 2. Ethyl cellulose 10 cps 5.60 %w/w

3. Talc 1.12 %w/w b) Drug coated pellets- Drag suspension was prepared using omeprazole, hydroxypropylmethyl cellulose, dibasic hydrogen phosphate, sodium lauryl sulfate and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with seal coated pellets prepared in step 1 (a) and it was coated by spraying the drag suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried in the fluidized bed processor. The resulting drug coated pellets were sieved through sieves 1000 μm and 600 μm. The pellets passed through sieve 1000 μm and retained on sieve 600 μm were used. Composition of drug coated pellets: 1. Seal coated pellets 49.31 %w/w

2. Omeprazole 32.46 %w/w

3. Sodium lauryl sulfate 0.71 %w/w

4. Dibasic hydrogen phosphate 0.45 %w/w 5. Hydroxypropyl Methylcellulose 17.07 %w/w

(E-15 LV) c) Barrier coated pellets- Barrier coating suspension was prepared using magnesium stearate, hydroxypropylmethyl cellulose, titanium dioxide and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with drag coated pellets from step 1(b) and it was coated by spraying the barrier coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting barrier coated pellets were sieved through sieves 1000 μm and 600 μm. The pellets passed through sieve 1000 μm and retained on sieve 600 μm were used.

Composition of barrier coated pellets:

1. Drug coated pellets 88.07 %w/w

2. Magnesium stearate 1.91 %w/w

3. Titanium dioxide 0.48 %w/w 3. Hydroxypropyl Methylcellulose 9.54 %w/w

(E-15 LV) d) Enteric coated pellets - Enteric coating suspension was prepared using methacrylic acid copolymer, type C USP-NF (Eudragit L 30 D-55), talc, polyethylene glycol 6000 and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with barrier coated pellets from step 1(c) and it was coated by spraying the enteric coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting enteric coated pellets were cured for 12 hours at temperature 38±2 °C and sieved through sieves 1180 μm and 600 μm. The pellets passed through sieve 1180 μm and retained on sieve 600 μm were used. Composition of enteric coated pellets:

1. Barrier coated pellets 43.57 %w/w 2. Eudragit L 30 D-55 51.77 %w/w

3. Polyethylene glycol 6000 1.55 %w/w

4. Talc 3.11 %w/w e) Film coated pellets - Film coating suspension was prepared using hydroxypropyl methylcellulose 15 cps, titanium dioxide and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with enteric coated pellets from step 1(d) and it was coated by spraying the film coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting enteric coated pellets-II were sieved through sieves 1180 μm and 600 μm. The pellets passed through sieve 1180 μm and retained on sieve 600 μm were used. Composition of film coated pellets:

1. Enteric coated pellets 96.76 %w/w

2. Hydroxypropyl methylcellulose 2.49 %w/w 15 cps 3. Titanium dioxide 0.75 %w/w

2) Prokinetic agent part a) Immediate release portion- Same as for Example 1 b) Sustained release portion- Same as for Example 1 c) Tablet compression- 100 mg granules prepared in step 2(a) and 80 mg granules prepared in step 2(b) were compressed to 180 mg weight bilayered tablets having a diameter of 5.56 mm.

3) Capsule filling

Proton pump inhibitor part equivalent to 20 mg omeprazole prepared in step 1 and prokinetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step 0 2 were filled in size 2 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in

Table 3:

Table 3: Dissolution profile of capsule

Example 4 1) Proton pump inhibitor part

Same as for Example 3 52) Prokinetic agent part a) Immediate release portion- Same as for Example 1 b) Sustained release portion- Same as for Example 1 c) Tablet compression- 100 mg granules prepared in step 2(a) and 80 mg granules prepared in step 2(b) were compressed to 180 mg weight bilayered tablets having a 0 diameter of 7.14 mm. 3) Capsule filling

Proton pump inhibitor part equivalent to 20 mg omeprazole prepared in step 1 and prokinetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step

2 were filled in size 00 hard gelatin capsule. 5 The dissolution rate of the dosage form prepared in step 3 is determined as shown in

Table 4:

Table 4: Dissolution profile of capsule

Example 5

1) Proton pump inhibitor part

Same as for Example 1

2) Prokinetic agent part a) Immediate release portion- 9.23 %w/w of domperidone was mixed with 78.77 %w/w of lactose and 0.08 %w/w ferric oxide red, and the mixture was granulated with 1.54 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 0.38 %w/w talc, 1.54 %w/w magnesium stearate, 7.69 %w/w crosspovidone (Polyplasdone XL 10), and 0.77 % w/w colloidal silicon dioxide. b) Sustained release portion- 28.24 %w/w domperidone was mixed with 9.15 %w/w of lactose monohydrate, 0.29 %w/w ferric oxide red, 0.24 %w/w magnesium stearate and 58.82 %w/w hydroxypropyl methylcellulose K4M and the mixture was dry granulated through roll compaction. The granules were sieved and mixed with 1.26 %w/w magnesium stearate, 1.5 %w/w talc and 0.5 %w/w colloidal silicon dioxide. c) Tablet compression- 65 mg granules prepared in step 2(a) and 85 mg granules prepared in step 2(b) were compressed to 150 mg weight bilayered tablets having a diameter of 5.56 mm.

3) Capsule filling Proton pump inhibitor part equivalent to 40 mg esomeprazole prepared in step 1 and proldnetic agent part equivalent to 30 mg domperidone prepared in step 2 were filled in size 2 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in Table 5:

Table 5: Dissolution profile of capsule

Example 6

1) Proton pump inhibitor part

Same as for Example 1

2) Prokinetic agent part

5 a) Immediate release portion- Same as for Example 5 b) Sustained release portion- Same as for Example 5 c) Tablet compression- 65 mg granules prepared in step 2(a) and 85 mg granules prepared in step 2(b) were compressed to 150 mg weight bilayered tablets having a diameter of 6.35 mm.

103) Capsule filling

Proton pump inhibitor part equivalent to 40 mg esomeprazole prepared in step 1 and prokinetic agent part equivalent to 30 mg domperidone prepared in step 2 were filled in size 0 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in 15 Table 6:

Table 6: Dissolution profile of capsule

Example 7

1) Proton pump inhibitor part

20 Same as for Example 3

2) Prokinetic agent part

Same as for Example 5

3) Capsule filling

Proton pump inhibitor part equivalent to 20 mg omeprazole prepared in step 1 and

25 prokinetic agent part equivalent to 30 mg domperidone prepared in step 2 were filled in size 2 hard gelatin capsule. The dissolution rate of the dosage form prepared in step 3 is determined as shown in Table 7:

Table 7: Dissolution profile of capsule

5 Example 8

1) Proton pump inhibitor part

Same as for Example 3

2) Proldnetic agent part Same as for Example 6

103) Capsule filling

Proton pump inhibitor part equivalent to 20 mg omeprazole prepared in step 1 and prokinetic agent part equivalent to 30 mg domperidone prepared in step 2 were filled in size 0 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in 15 Table 8:

Table 8: Dissolution profile of capsule

Example 9 1) Proton pump inhibitor part Same as for Example 3 2) Prokinetic agent part a) Drug coated pellets- Drug coating suspension was prepared using mosapride citrate dihydrate, hydroxypropyl methylcellulose 6 cps and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with microcrystalline cellulose (Celphere CP 203) and it was coated by spraying the drag suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting drug coated pellets were sieved through sieves 425 μm and 250 μm. The pellets passed through sieve 425 μm and retained on sieve 250 μm were used. Composition of drug coated pellets: 1. Microcrystalline cellulose 37.98 %w/w

(Celphere CP 203)

2. Mosapride citrate 44.30 %w/w dihydrate

3. Hydroxypropyl methylcellulose 17.72 %w/w (6 cps) b) Sustained release pellets- Sustained release coating suspension was prepared using ammonio methacrylate copolymer, type A USP-NF (Eudragit RL 30 D), ammonio methacrylate copolymer, type B USP-NF (Eudragit RS 30 D), triethyl citrate, silicon dioxide (Syloid 244FP) and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with drag coated pellets from step 1(a) and it was coated by spraying the sustained release coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting sustained release pellets were cured for 13 hours at 40°C and sieved through sieves 600 μm and 250 μm. The pellets passed through sieve 600 μm and retained on sieve 250 μm were used. Composition of sustained release pellets: 1. Drag coated pellets 66.18 %w/w

2. Eudragit RS 30 D 24.51 %w/w

3. Eudragit RL 30 D 4.90 %w/w

4. Triethyl citrate 2.65 %w/w 5. Syloid 244 FP 1.76 %w/w

3) Capsule filling

Proton pump inhibitor part equivalent to 20 mg omeprazole prepared in step 1 and prokinetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step 2 were filled in size 3 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in Table 9:

Table 9: Dissolution profile of capsule

Example 10

1) Proton pum : a) Drug coated pellets- Same as for example 1 b) Barrier coated pellets- Same as for example 1 c) Enteric coated pellets-I - Same as for example 1 d) Enteric coated pellets-II - Same as for example 1 e) Lubricated blend- 28.86 %w/w of enteric coated pellets-II as prepared in step 1(d), 63.14 %w/w microcrystalline cellulose (Avicel PH 200), 3.00 %w/w of copolyvidone (Kollidon NA 64), 3.00 %w/w crospovidone (Polyplasdone XL 10), 1.0 %w/w talc, 0,50 %w/w colloidal silicon dioxide and 0.50 %w/w magnesium stearate were mixed. f) Tablet compression- 600 mg lubricated blend prepared in step 1(e) was compressed to oblong tablet of 17.5 X 6.8 mm.

2) Prokinetic agent part 5 Same as for example 6

3) Capsule filling Tablets prepared in step 1(f) and step 2 were filled in size 00 hard gelatin capsule.

Table 10:

Table 10: Dissolution profile of capsule

Example 11 1) Proton pump inhibitor part Same as for example 1 102) Proldnetic agent part Same as for example 9

3) ubrieated blend

23.09 %w/w of proton pump inhibitor part (equivalent to 40 mg esomeprazole) as prepared in step 1, 5.70 %w/w of prokinetic agent (equivalent to 15 mg mosapride) part 15 as prepared in step 2, 63.3 %w/w microcrystalline cellulose (Avicel PH 200), 3.00 %w/w of copolyvidone (Kollidon NA 64), 3.00 %w/w crospovidone (Polyplasdone XL 10), 1.00 %w/w talc, 0.5 %w/w colloidal silicon dioxide and 0.5 %w/w magnesium stearate^'were mixed.

4) Tablet compression

20 750 mg lubricated blend prepared in step 3 was compressed to oblong tablet of 17.5 X 6,8 mm. The dissolution rate of the dosage form prepared in step 3 is determined as shown in

25 Table 11:

Table 11: Dissolution profile of tablet

Example 12

51) Proton pump inhibitor part

Same as for example 10

2) Proldnetic agent part 30.00 %w/w domperidone was mixed with 36.00 %w/w of lactose monohydrate, and 30.00 %w/w hydroxypropyl methylcellulose K4M and the mixture was granulated with 0 2.00 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 0.50 %w/w magnesium stearate, 1.00 %w/w talc and 0.5 %w/w colloidal silicon dioxide.

Bilayered tablet compression Proton pump inhibitor part equivalent to 20 mg esomeprazole prepared in step l(to 5 form layer 1) and prokinetic agent part equivalent to 30 mg domperidone prepared in step 2 (to form layer 2) were compressed to form a bilayered round tablet of 7.14 mm diameter.

The dissolution rate of the dosage form prepared in step 3 determined as shown in Table 112: 0

Table 12: Dissolution profile of tablet

Example 13 1) Proton pump inhibitor part

Same as for example 10 52) Prokinetic agent part a) Immediate release portion- Same as for Example 1 b) Sustained release portion- Same as for Example 1 3) Three layered tablet compression

Proton pump inhibitor part equivalent to 20 mg esomeprazole prepared in step 1 (to 0 form layer 1), 100 mg of prokinetic part prepared in step 2(a) (to form layer 2) and 80 mg of prokinetic part prepared in step 2(b) (to form layer 3) were compressed to form a three layered round tablet of 7.14 mm diameter. Both the proldnetic parts are together equivalent to 15 mg mosapride.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in 5 Table 13:

Table 13: Dissolution profile of tablet

Example 14

1) Proton pump inhibitor part 0 Same as for example 10

2) Prokinetic agent part Same as for example 2

3) Inlay tablet compression Proton pump inhibitor part equivalent to 40 mg esomeprazole prepared in step 1 (to form outer part of the inlay tablet) and prokinetic agent part prepared in step 2 (to form inner part of inlay tablet) were compressed to form a round inlay tablet of 12.7 mm diameter.

The compression is done in such a manner that the resultant tablet has inner portion covered by the outer portion from all the sides except the top surface that remains uncovered and the level of the inner portion and the outer portion is on the same surface (as shown in fig. 7).

The dissolution rate of the dosage form prepared in step 3 is determined as shown in Table 14:

Table 14: Dissolution profile of tablet

Exam le 15

1) Proton pump inhibitor part Same as for example 10

2) Proldnetic agent part Same as for example 2

3) Tablet-in-tablet compression

Proton pump inhibitor part equivalent to 40 mg esomeprazole prepared in step 1 (to form the outer part of the tablet-in-tablet) and prokinetic agent part prepared in step 2

(to form the inner part of the tablet-in-tablet) were compressed to form a round inlay tablet of 12.7 mm diameter.

The compression is done in such a manner that the resultant tablet has inner portion covered by the outer portion from all the sides (as shown in fig. 8). The dissolution rate of the dosage form prepared in step 3 is determined as shown in

Table 15: Table 15: Dissolution profile of tablet

Example 16 1) Proton pump inhibitor part a) Rabeprazole base granules- 53.84 %w/w of magnesium oxide light was mixed with 44.54 %w/w of mannitol and 1.54 %w/w crospovidone (Polyplasdone XL 10) and the mixture was granulated using 0.08 %w/w sodium hydroxide and then dried. The sodium hydroxide was dissolved in water. The granules were sieved. b) Rabeprazole granules- 12.50 %w/w rabeprazole sodium was mixed with 78.74 %w/w of rabeprazole sodium base granules prepared in step 1(a), and the mixture was granulated with 3.13 %w/w povidone in fluidized bed processor. The binder was dissolved in water. The dried granules were sieved and mixed with 2.50 %w/w magnesium stearate and 3.13 %w/w crospovidone (Polyplasdone XL 10). c) Tablet compression- Proton pump inhibitor part equivalent to 10 mg rabeprazole sodium prepared in step 1 (b) was compressed to form a round tablet of 6.35 mm diameter. d) Barrier coated tablets - Barrier coating suspension was prepared using hydroxypropyl methylcellulose 15 cps, ethyl cellulose 10 cps, talc, diefhylpthalate, colloidal silicon dioxide, isopropyl alcohol and methylene chloride. A perforated tablet coating machine was charged with tablets from step 1(c), it was coated by spraying the barrier coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the coating machine. Composition of barrier coated tablets: 1. Tablets 96.70 %w/w

2. Hydroxypropyl methylcellulose 2.02 %w/w (15 cps)

3. Ethyl cellulose 10 cps 0.50 %w/w

4. Talc 0.43 %w/w

5. Diefhylpthalate 0.30 %w/w

6. Colloidal silicon dioxide 0.05 %w/w

e) Enteric coated tablets - Enteric coating suspension was prepared using hydroxypropylmethylcellulose pfhalate, talc, titanium dioxide, ferric oxide yellow, diefhylpthalate, methanol and methylene chloride. A perforated pan tablet coating

10 machine was charged with barrier coated tablets from step 1(d) and were coated by spraying the enteric coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the tablet coating machine.

Composition of enteric coated tablets:

15 1. Barrier coated tablets 86.31 %w/w

2. Hydroxypropyl methylcellulose 10.43 %w/w P halate

3. Talc 0.86 %w/w

4. Ferric oxide yellow 0.12 %w/w

20 5. Diethylpyhalate 1.04 %w/w

6. Titanium dioxide 1.24 %w/w

2) Prokinetic agent part Same as for example 2 253) Capsule filling

Proton pump inhibitor part equivalent to 10 mg rabeprazole sodium prepared in step 1 and prokinetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step 2 were filled in size 00 hard gelatin capsule.

The dissolution rate of the dosage form prepared in step 3 is determined as shown in 30 Table 16:

Table 16: Dissolution profile of capsule

Example 17

A sustained release of formulation equivalent to proldnetic agent part of the example 2 (test formulation) containing 15 mg mosapride citrate (administered once a day) and conventional tablets of mosapride citrate 3X5 mg (administered three times a day) (reference formulation) were administered to 12+2 healthy volunteers in an open, randomized, two treatment, two sequence, two period, crossover study. Samples of total 11 volunteers was analyzed. The plasma drug concentration of test and reference formulation are presented in Table 17 and pharmacokinetic data in Table 18.

Table 18: Pharmacokinetic parameters of mosapride citrate

From the analysis of study results it is concluded that the test formulation of mosapride citrate sustained release 15mg tablet (given once in 24 hrs) has sustained release characteristics and has dosage equivalence with reference formulation, that is, conventional release mosapride citrate 5mg tablet (given three times in 24 hrs). Example 18

A delayed release of formulation equivalent to proton pump inhibitor part of the example 15 (test formulation) containing 40 mg esomeprazole and a marketed delayed release tablets of esomeprazole 40 mg (both administered once a day) (reference formulation) were administered to 12 healthy volunteers in open, randomized, two treatment, two sequence, two period, crossover study. The plasma drag concentration of test and reference formulation are presented in Table 19 and pharmacokinetic data in Table 20.

Table-19: Plasma concentration of esomeprazole

Table 20: Pharmacokinetic parameters of esomeprazole

The analysis of study results of comparative bioavailability study of esomeprazole tablets, it is concluded that test formulation of esomeprazole (1 x 40 mg) tablets is bioequivalent with reference formulation esomeprazole (1 x 40mg) tablets. Example 19 1) Proton pump inhibitor part a) Esomeprazole granules : 24.75 %w/w esomeprazole magnesium trihydrate was mixed with 66.25 %w/w of mannitol and the mixture was granulated with 1.5 %w/w hydroxypropyl methylcellulose. The binder was dissolved in water. The dried granules were sieved and mixed with 3.0 %w/w of crospovidone (Polyplasdone XL-10), , 2.0

5 %w/w talc, 0.5 %w/w colloidal silicon dioxide and 2.0 %w/w magnesium stearate. b) Tablet compression- Proton pump inhibitor part equivalent to 20 mg esomeprazole prepared in step 1 (a) was compressed to form a round tablet of 6.35 mm diameter. c) Barrier coated tablets - Barrier coating suspension was prepared using hydroxypropyl methylcellulose 15 cps, magnesium stearate and purified water. A perforated tablet 10 coating machine was charged with tablets from step 1(b) and coating done by spraying the barrier coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the coating machine.

Composition of barrier coated tablets: 15 1. Tablets 97.45 %w/w

2. Hydroxypropyl methylcellulose 2.13 %w/w (15 cps)

3. Magnesium stearate 0.42 %w/w d) Enteric coated tablets - Enteric coating suspension was prepared using methacrylic acid 20 copolymer, Type C (Eudragit L30D - 55), triethyl citrate, talc, titanium dioxide, ferric oxide red and purified water. A perforated pan tablet coating machine was charged with barrier coated tablets from step 1(c) and were coated by spraying the enteric coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the tablet coating machine. 25 Composition of enteric coated tablets:

1. Barrier coated tablets 83.52 %w/w

2. Methacrylic acid copolymer, 7.43 %w/w Type C (Eudragit L30D - 55)

3. Triethyl citrate 0.74 % w/w

30 - 3. Talc 7.42 %w/w

'4. Titanium dioxide 0.74 % w/w

4. Ferric oxide red 0.15 %w/w

2) Prokinetic agent part a) Immediate release portion- 8.98 %w/w of domperidone maleate was mixed with 83.27

%w/w of lactose and 0.01 %w/w ferric oxide red, and the mixture was granulated with 1.5 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 0.5 %w/w talc, 0.5 %w/w magnesium stearate, 5.0 %w/w crospovidone 5 (Polyplasdone XL 10), and 0.24 % w/w colloidal silicon dioxide. b) Sustained release portion- 29.09 %w/w domperidone maleate was mixed with 19.60

%w/w of lactose monohydrate, 2.38 %w/w ferric oxide red, 0.19 %w/w magnesium stearate and 45.48 %w/w hydroxypropyl methylcellulose K4M and the mixture was dry granulated through roll compaction. The granules were sieved and mixed with 1.26 10 %w/w magnesium stearate, 1.5 %w/w talc and 0.5 %w/w colloidal silicon dioxide. c) Tablet compression- 65 mg granules prepared in step 2(a) and 85 mg granules prepared in step 2(b) were compressed to 190 mg weight bilayered tablets having a diameter of 6.35 mm. 3) Capsule filling

15 Proton pump inhibitor part equivalent to 40 mg esomeprazole (two tablets of 20 mg strength each) prepared in step 1 and prokinetic agent part equivalent to 30 mg domperidone prepared in step 2 were filled in size 0 hard gelatin capsule. The dissolution rate of the dosage form prepared in step 3 was determined (Table 21) Table 21: Dissolution profile of capsule

Example 20 1) Proton pump inhibitor part a) Seal coated pellets (I)- Seal coating (I) suspension was prepared using ethyl cellulose 10 25 cps, talc, methanol and methylene chloride. A fluidized bed processor of wurster type

(manufactured by Glatt, Germany) was charged with sugar globules and it was coated by spraying the seal coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting drug coated pellets were sieved through sieves 850 μm and 600 μm. The pellets passed through sieve 850 μm and retained on 5 sieve 600 μm were used.

Composition of seal coated pellets: 1. Sugar globules 93.28 %w/w

2. Ethyl cellulose 10 cps 5.60 %w/w

3. Talc 1.12 %w/w S) Seal coated pellets (II)- Seal coating (II) suspension was prepared using magnesium oxide (light), povidone (K-30), talc and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with seal coated pellets (I) from step 1(a) and it was coated by spraying the seal coating (I) suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and 5 then drying was carried out in the fluidized bed processor. The resulting barrier coated pellets were sieved through sieves 850 μm and 600 μm. The pellets passed through sieve 600 μm and retained on sieve 850 μm were used. Composition of barrier coated pellets:

1. Seal coated pellets (I) 95.24 %w/w 0 2. Magnesium oxide (light) 2.38 %w/w

3. Povidone (K-30) 1.90 %w/w

4. Talc 0.48 %w/w c) Drug coated pellets- Drug suspension was prepared using Rabeprazole sodium, povidone (K-30), sodium hydroxide, magnesium oxide (light) and purified water. A fluidized bed 5 processor of wurster type (manufactured by Glatt, Germany) was charged with seal coated (II) pellets from step 1(b) and coating done by spraying the drug suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting drag coated pellets were sieved through sieves 850 μm and 600 μm. The pellets passed 0 through sieve 850 μm and retained on sieve 600 μm were used. Composition of drug coated pellets: 1. Seal coated (II) pellets 55.26 %w/w

2. Rabeprazole sodium 27.62 %w/w 3. Povidone (K-30) 11.05 %w/w

4. Sodium hydroxide 0.55 %w/w

5. Magnesium oxide (light) 5.52 %w/w d) Barrier coated pellets- Barrier coating suspension was prepared using hydroxypropyl methylcellulose (E-15 LV), magnesium oxide (light), magnesium stearate and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with drug coated pellets from step 1(c) and coating done by spraying the barrier coating suspension. The spraying operation was stopped when the specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting barrier coated pellets were sieved through sieves 1.18 mm and 600 μm. The pellets passed through sieve 1.18 mm and retained on sieve 600 μm were used.

Composition of barrier coated pellets:

1. Drug coated pellets 86.95 %w/w 5 2. Hydroxypropyl Methylcellulose 10.87 %w/w

(E-15 LV) 3. Magnesium oxide (light) 1.09 %w/w

3. Magnesium stearate 1.09 %w/w

Qe) Enteric coated pellets - Enteric coating suspension was prepared using methacrylic acid copolymer, type C, USP-NF (Eudragit L30D - 55), talc, polyethylene glycol 6000 and purified water. A fluidized bed processor of wurster type (manufactured by Glatt, Germany) was charged with barrier coated pellets from step 1(d) and coating done by spraying the enteric coating suspension. The spraying operation was stopped when the 5 specified amount of bulk liquid had been sprayed, and then drying was carried out in the fluidized bed processor. The resulting enteric coated pellets-I were sieved through sieves 1.18 mm and 600 μm. The pellets passed through sieve 1.18 mm and retained on sieve 600 μm were used.

Composition of enteric coated pellets: 0 1. Barrier coated pellets 66.66 %w/w

2. Eudragit L30D - 55 25.65 %w/w

3. Polyethylene glycol 6000 2.56 %w/w

4. Talc 5.13 %w/w ) Prokinetic agent part a) Immediate release portion- 3.29 %w/w of mosapride citrate dihydrate was mixed with

58.62 %w/w of lactose monohydrate, 29.89 %w/w microcrystalline cellulose, 0.02 %w/w ferric oxide red, 0.08 %w/w ferric oxide yellow and the mixture was granulated 5 with 3.10 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 1.03 %w/w magnesium stearate, 3.45 %w/w croscarmellose sodium, and 0.52 % w/w colloidal silicon dioxide. b) S stained release portion- 13.90 %w/w of mosapride citrate dihydrate was mixed with

47.98 %w/w of lactose monohydrate and 31.25 %w/w hydroxypropyl methylcellulose 10 K4M and the mixture was granulated with 5.00 %w/w povidone. The binder was dissolved in water. The dried granules were sieved and mixed with 1.25 %w/w magnesium stearate, 0.62 %w/w colloidal silicon dioxide. c) Tablet compression- 145 mg granules prepared in step 2(a) and 80 mg granules prepared in step (b) were compressed to 225 mg weight bilayered tablets having a diameter of 15 5.56 mm.

3) Capsule filling

Proton pump inhibitor part equivalent to 20 mg Rabeprazole sodium prepared in step 1 and prokinetic agent part equivalent to 15 mg mosapride citrate anhydrous prepared in step 2 were filled in size 1 hard gelatin capsule. 20 The dissolution rate of the dosage form prepared in step 3 was determined (Table 1) Table 22: Dissolution profile of capsule

REFERENCE CITED Patents

25 US 2001/0051185 Al 12/2001 Joaquina F.

97/25065 12/1996 Depui H. et. al. WIPO 00/51583 03/2000 Rubin P.D. et. al. WIPO

00/51584 03/2000 Rubin P.D. et. al. WIPO

96/29055 03/1996 Cox G. WIPO

99/51209 03/1999 Ting R. WIPO

5 1060743 A106/1999 Chao S.^' EP

98/29095 12/1997 Clancy M. et. al. WIPO

Articles

1. Szarka L. A. and Locke G.R. Post Graduate Medicine - 1999; 105 (7): 88-105.

2. Scoot L. J., Dunn C J. et al. Drugs 2002; 62 (7): 1091-1118. 103. Mosapride Citrate: website - www.micromedex.com

4. Mosapride Citrate; Drags of the future 1993; 18(6): 513-515.

5. Salcashita M., Yamaguchi T, Miyazaki H. et al. Drugs Res.-1993; 43(8): 867-872.

6. Carlsson L, Amos G.J. Anderson B et al. J Pharmacol Expt ther 1997;282(1): 220- 227.

15 OTHER RELATED DOCUMENTS

Patents

US Patent Documents

US 6132770 02/1997 Lundberg PJ.

US 5817338 06/1995 Bergstrand P J.A. et al.

20 96/01623 06/1995 Bergstrand PJ. A. et al. WIPO

25

30

Claims

Claims:

1. A pharmaceutical compositions for once a day oral administration, comprising at least one delayed release component, wherein said delayed release component comprises a proton pump inhibitor, said composition further including at least one immediate release and/or a sustained release prokinetic agent.

2. A pharmaceutical composition according to claim 1 wherein the dosage form is a capsule comprising sustained release particles of a prokinetic agent and delayed release particles of a proton pump inhibitor.

3. A pharmaceutical composition according to claim 1 wherein the dosage form is a capsule comprising sustained release particles of a proldnetic agent and delayed release tablet of a proton pump inhibitor.

4. A pharmaceutical composition according to claim 1 wherein the dosage form is a capsule comprising sustained release matrix tablet of a prokinetic agent and delayed release particles of a proton pump inhibitor. 5. A pharmaceutical composition according to claim 1 wherein the dosage form is a capsule comprising sustained release matrix tablet of a proldnetic agent and delayed release tablet of a proton pump inhibitor.

6. A pharmaceutical composition according to claim 4 and 5 wherein the sustained release matrix tablet is in the form of bilayered tablet having immediate release layer and sustained release layer.

7. A pharmaceutical composition according to claim 1 wherein the dosage form is a multiparticulate tablet comprising sustained release particles of a proldnetic agent and delayed release particles of a proton pump inhibitor.

8. A pharmaceutical composition according to claim 7 wherein the multiparticulate tablet is water dispersible.

9. A pharmaceutical composition according to claim 1 wherein the dosage form is a bilayered tablet comprising sustained release layer of a prokinetic agent and a delayed release layer of consisting of particles of a proton pump inhibitor.

10. A pharmaceutical composition according to claim 1 wherein the dosage form is a multilayered tablet comprising a sustained release layer of a prokinetic agent, an immediate release layer of a prokinetic agent and a layer comprising of delayed release particles of a proton pump inhibitor.

11. A pharmaceutical composition according to claim 1 wherein the sustained release prokinetic agent part is in the form of a single layer matrix tablet.

12. A pharmaceutical composition according to claim 1 wherein the sustained release prokinetic agent part is in the form of a bilayered matrix tablet comprising a sustained release layer and an immediate release layer.

13. A pharmaceutical composition according to claim 6 and 12, wherein said bilayered matrix tablet comprises about 0 to 50 % by weight of total prokinetic agent in immediate release layer and about 100 to 50% by weight of total prokinetic agent in sustained release layer. 14. A pharmaceutical composition according to claim 13 wherein said bilayered matrix tablet comprises preferably about 5 to 45 % by weight of total prokinetic agent in immediate release layer and about 95 to 55% by weight of total prokinetic agent in sustained release layer.

15. A pharmaceutical composition according to claim 13 wherein said bilayered matrix tablet comprises more preferably about 10 to 40 % by weight of total prokinetic agent in immediate release layer and about 90 to 60% by weight of total prokinetic agent in sustained release layer.

16. A pharmaceutical composition according to claim 11 and 12 wherein the sustained release matrix of prokinetic agent comprises a hydrophilic polymer. 17. A pharmaceutical composition according to claim 16 wherein the hydrophilic polymer is selected from hydroxyprepylmethyl cellulose, hydroxypropyl cellulose , poly (e hylene oxide), poly(vinyl alcohol), xanfhan gum, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate or mixtures thereof.

18. A pharmaceutical composition according to claim 16 wherein said hydrophilic polymer comprises hydroxyprepylmethyl cellulose.

19. A pharmaceutical composition according to claim 1 wherein the sustained release prokinetic agent part is in the form of multiparticulate system.

20. A pharmaceutical composition according to claim 19 wherein the sustained release particles of prokinetic agents comprise of core coated with rate controlling membrane(s).

21. A pharmaceutical composition according to claim 20 wherein the core comprises of prokinetic agent along with commonly used water soluble and/or water insoluble and/or water dispersible and/or water disintegrable excipients.

22. A pharmaceutical composition according to claim 20 wherein the prokinetic agent and excipient(s) are build up on a central inert nucleus.

23. A pharmaceutical composition according to claim 20 wherein the rate controlling membrane is made up of alone or effective combination of pharmaceutically acceptable film-forming polymers of varying water solubility and permeability.

24. A pharmaceutical composition according to claim 20 wherein the rate controlling polymer is selected from alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic and methacrylic acids and esters thereof, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene tereph halates, polyvinyl esters, polyvinylpyrrolidone, polyglycolides, polysiloxanes and polyurefhanes and co-polymers thereof.

25. A pharmaceutical composition according to claim 20 wherein the rate controlling membrane contains ammonio methacrylate co-polymers. 26. A pharmaceutical composition according to claim 20 wherein comprising a blend of two or more types of controlled release particles of prokinetic agent having different release profiles.

27. A pharmaceutical composition according to claim 20 wherein the controlled release particles of said prokinetic agent comprises an additional enteric coat over the rate controlling membrane.

28. A pharmaceutical composition according to claim 1 wherein the delayed release proton pump inhibitor is in the form of multiparticulate system in the form of enteric coated particles.

29. A pharmaceutical composition according to claim 1 wherein the delayed release proton pump inhibitor is in the form of enteric coated tablet.

30. A pharmaceutical composition according to claim 1 wherein the proton pump inhibitor is selected from, but not limited to, benzimidazole derivatives, such as omeprazole, rabeprazole, pantoprozole, lansoprazole, pariprazole, leminoprazole, nepaprazole, tenatoprazole, esomeprazole or active metabolites thereof. 31. A pharmaceutical composition according to claim 1 wherein the proton pump inhibitor is omeprazole.

32. A pharmaceutical composition according to claim 1 wherein the proton pump inhibitor is esomeprazole.

33. A pharmaceutical composition according to claim 1 wherein the proton pump inhibitor is rabeprazole.

34. A pharmaceutical composition according to claim 1 wherein the prokinetic agent is selected from, but not limited to, cisapride, dazopride, mosapride, exepanol, lintopride, motilin, idremcinal, mitemcinalum, neurofrophin-3, KC-11458, MKC-733, Braintree-851, zacopride, ecabapide, pracalopride, fedotozine, cinitapride, itopride, polycarbophil, tegaserod, INKP-100, diacol, metoclopramide and domperidone.

35. A pharmaceutical composition according to claim 1 wherein the prokinetic agent is mosapride. 36. A pharmaceutical composition according to claim 1 wherein the prokinetic agent is domperidone.

37. Once a day orally administered pharmaceutical composition comprising a prokinetic agent in sustained release matrix tablet.

38. A composition as claimed in claim 37 wherein said tablet is made by wet granulation method and/or dry granulation method.

39. A composition as claimed in claim 37 or 38 comprising 10 - 75 %w/w release controlling agent.

40. A composition as claimed in claim 39 wherein the release controlling agent is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), poly (ethylene oxide), poly(vinyl alcohol), xanthan gum, carbomer, carrageenan, carboxymethyl cellulose, sodium alginate or mixture thereof.

41. A composition as claimed in any one of claims 37 to 40 wherein the sustained release matrix tablet is a bilayered tablet comprising immediate release and sustained release layer. 42. - A composition as claimed in claim 41 wherein the sustained release matrix tablet comprises 5 to 45 % by weight of total prokinetic agent in immediate release layer and 95 to 55 % by weight of total prokinetic agent in sustained release layer.

43. A process for the preparation of once a day orally administered pharmaceutical composition which comprises preparing a sustained release matrix tablet by wet granulation method and/or dry granulation method, wherein the tablet includes a prokinetic agent in said sustained release matrix tablet.

44. A process as claimed in claim 43 comprising 10 - 75 %w/w release controlling agent.

MISSING AT THE TIME OF PUBLICATION

from 5 to 70% proldnetic agent is released in one hour from 15 to 80 % prokinetic agent is released in four hours from 25 to 90 % prokinetic agent is released in eight hours from 35 to 100 % prokinetic agent is released in twelve hours.

54. A pharmaceutical composition according to claim 1 wherein the proton pump inhibitor of the pharmaceutical composition exhibits the following in vitro dissolution profile in 0.1 N HCl or simulated gastric fluid when measured as per the specified conditions :- not more than 15 % proton pump inhibitor is release in two hours.

55. A pharmaceutical composition according to claim 1 wherein the proton pump inhibitor of the pharmaceutical composition exhibits the following in vitro dissolution profile in simulated intestinal fluid or appropriate buffer when measured as per the specified conditions :- not less than 75 % proton pump inhibitor is release in 45 minutes.

56. A pharmaceutical composition according to claim 1 to 5 wherein the unit dosage form capsule is prepared by following steps:

Step-1 : Preparation of proton pump inhibitor part.

Step-2: Preparation of prokinetic agent part.

Step-3: Preparation of unit dosage by filling_the product obtained from step-1 and step-2 into capsule. 57. A pharmaceutical composition according to claim 1, 7, 9 and 10 wherein the unit dosage form tablet is prepared by following steps:

Step-1 : Preparation of proton pump inhibitor part.

Step-2: Preparation of prokinetic agent part.

Step-3: Preparation of unit dosage while combining the product obtained from step-1 and step-2.

58. A method for treating which comprises administering to a patient in need thereof a pharmacutical composition as claimed in claim 1.

59. A method for treating which comprises administering to a patient in need thereof a pharmaceutical composition as claimed in claim 37. 60. A method for treating which comprises administering to a patient in need thereof a pharmacutical composition as claimed in claim 56^' or 57.

61. Use of the composition as claimed in any preceding claim for the preparation of a medicament for the freatment of peptic ulcer disease and gasfro-esophageal reflux disorder.